CYCLOTHIAZIDE DIFFERENTIALLY MODULATES DESENSITIZATION OF LPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID RECEPTOR SPLICE VARIANTS

Agonist responses for flip splice variants of the lpha-amino-3-hydroxy -5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR-A, - C, and -D are more strongly potentiated by cyclothiazide than are thos e for the flop forms. Cyclothiazide shows both greater efficacy and hi gher apparent affinity for potentiation of GluR-A(flip) versus GluR-A( flop). Consistent with higher affinity for the Rip splice variant, rec overy from potentiation by cyclothiazide proceeds 30 times more slowly for GluR-AR(flip) than for GluR-A(flop). In the presence of 300 mu M cyclothiazide a 6-fold leftward shift in the kainate dose-response cur ve for GluR-A(flip) but not GluR-A(flop) additionally contributes to a difference in potentiation for these splice variants. Although contro l responses to glutamate show strong desensitization for both splice v ariants of GluR-A, in the presence of 100 mu M cyclothiazide desensiti zation is strongly attenuated for GluR-A(flip), whereas for GluR-A(flo p) desensitization remains pronounced but with a rate of onset slowed 50-fold, compared with control. In heteromeric AMPA receptors formed f rom GluR-A and GluR-B, the flip splice variants are dominant for contr olling both recovery from potentiation of responses to kainate and blo ck of desensitization of responses to glutamate. Our results suggest t hat the flip/flop module could directly contribute to the binding site for cyctothiazide, raising the possibility that this site is located in an extracellular receptor domain.